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Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms
J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang1§, P. Cui2§, Q. Luo1, L. Wang1, S. Li1, X. Zhang1* 1
Shenyang Pharmaceutical University, Wen Hua Road, No. 103, Shenyang 110016, Liaoning Province, China 2 The first hospital of China Medical University, Shenyang 110001, Liaoning Province, China § These authors contributed equally to this work. *Correspondence: [email protected]
The purpose of this work was to develop optimized press-coated tablets of salbutamol sulfate using polyethylene glycol 6000 (PEG 6000)-Eudragit S100 dispersion blends in the outer shell. To facilitate the direct application of the Eudragit S100 and PEG 6000 onto the inner core, solid Eudragit S100 powder was mixed with PEG 6000 by fusion method. The optimized, pulverized dispersions of polymer blends were evaluated by various methods of characterization, including differential scanning calorimetry, X-ray diffraction and spectroscopy. The press-coated tablets containing salbutamol sulfate in the inner core were prepared by compression-coating with (PEG 6000)-Eudragit S100 dispersion blends as the outer layer in different ratios. The amount of outer layer on the delayed drug release was investigated. The press-coated tablets release were evaluated in 0.1 M HCl for the first 2 h and then in pH 6.8 phosphate buffer for 7 h. The mechanism of delayed drug release is based on erosion of the out layer blends. The results showed the 0.15 g of PEG 6000/ Eudragit S100 (2:1) in the outer shell achieving delayed release of drug in vitro as well as in the plasma of beagle dogs. Key words: Salbutamol sulfate – Press-coated tablet – PEG 6000-Eudragit S100 blends – Dissolution – Delayed release – In vitro, in vivo – Beagle dogs.
Salbutamol sulfate (STS) is one of the most widely used drugs for the treatment of bronchial asthma, chronic bronchitis and emphysema [1]. As an adrenergic agonist, it is an effective bronchodilator following peroral administration. The drug undergoes extensive first-pass metabolism and thus requires frequent administrations by the oral route. Asthma is a chronic disease, and since most of the patients suffer nocturnally, it is inconvenient for patients to take the medicine at midnight [2]. There is a need for a special designed drug delivery system which can maintain concentrations of STS at a therapeutic level for a long time. Delayed drug delivery systems can be categorized into a sitespecific or time-controlled system. A site specific system is typically controlled by environmental factors, such as pH or enzymes [3, 4]. In time-controlled systems, drug release is controlled primarily by the design of the delivery system. Time-controlled systems are characterized by two release phases. An initial phase when little drug is released, followed by a second phase, during which the drug is released completely within a short period of time after a lag [5]. Time-controlled release formulation is the preferred approach for the treatment of circadian diseases such as asthma, rheumatic arthritis or inflammation. Time-controlled release formulation generally has a rapid-release tablet core encompassed by a barrier layer formed by press-coating, polymer coating or a combination of both [6]. Compared with polymer coating, press-coating technique has the advantage of not needing to use solvents and a relatively short manufacturing process. Delayed drug release from press-coated tablets depends on the thickness and the composition of the barrier layer. Generally, the thicker the barrier layer, the longer the time there is for drug release [7]. Composition of the barrier layer controls the mechanism affecting the drug release. Polymer blends could be the solution for the creation of new materials, exhibiting the appropriate flexibility for the adjustment of the drug release [8]. In the current study, polymer blends consisting of polyethylene glycol 6000 (PEG 6000) and Eudragit S100 are investigated to create a
system that can be modified by taking advantage of the hydrophilicity of PEG 6000 and hydrophobicity of Eudragit S100 in 0.1 M HCl. The pulverized dispersions of polymer blends were mechanically much stronger than the physical mixture of Eudragit S100 and PEG 6000. The combination and application of PEG 6000-Eudragit S100 blends as press-coating material is novel in the drug delivery field, since there is no such report to date in the literature. The press-coated tablet does not release the drug in the stomach due to the acid resistance of the outer coating layer containing Eudragit S100. After gastric emptying, the intestinal fluid begins to slowly erode the press-coated PEG 6000-Eudragit S100 layer, and when the erosion front reaches the core tablet, rapid drug release occurs. The delayed release time can be controlled by the weight or composition of the PEG 6000-Eudragit S100 miscible blends for the outer layer. The dog is widely used for in vivo evaluation of delayed-release formulation because of its reported similarity in gastrointestinal anatomy and motility. The use of the dog is further advantageous in terms of being less expensive and more readily available than conducting studies in human volunteers [9, 10]. A further objective of the present study therefore was to investigate in vivo performance of the STS press-coated tablet. The purpose of this investigation was to prepare PEG 6000-Eudragit S100 polymer blends used in delayed release formulations of STS press-coated tablets. The internal core contains the active pharmaceutical ingredient (STS) while the external homogeneous coating layer is composed of various PEG 6000-Eudragit S100 blends made by fusion method that adjust to the initiation of STS release through their rupture. PEG 6000 was used as a hydrophilic carrier to prepare the dispersions due to its low melting point, high viscosity, rapid solidification rate and wide compatibility. Eudragit S100 is an enteric coating polymer, composed of methyl-methacrylate and methacrylic acid. This polymer is soluble at pH-values higher than 7.0. It is slowly soluble in the region of the digestive tract where juices are neutral to weakly alkaline. The coating layer consisted of Eudragit S100, resistant to the conditions in the stomach, and PEG 6000 as hydrophilic carrier, 335
J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
to ensure the complete release of drug within the pH range of 6.0-7.0 during transit through the small intestine. The objective of the current study was to evaluate the in vitro performance of the press-coated tablets for delayed release formulation and the in vivo behavior after an oral administration to beagle dogs under fast condition.
6. Coating core tablets with PEG 6000-Eudragit S100 blends
The active core contains active STS while the coating layer is composed of the various polymer blends of Eudragit S100 with PEG 6000. The press coated tablets were prepared by direct compression technique. Eudragit S100 with PEG 6000 pulverized dispersions were accurately weighed. 0.5 % magnesium stearate as a lubricant based on out layer weight was added to the dried granules and passed through a sieve of 500 μm aperture size and mixed for 5 min. Half the amount of polymer granules was filled into the die, and a core tablet was placed at the center on the polymer. Then, the remaining half was filled in the die, and the total contents were compressed to form a biconvex tablet with a diameter of 9 mm, at a compression force of 3 kg/mm2 using single punch tablet machine. Thickness of coating layer is about 1.3-1.4 mm.
I. Materials and Methods 1. Materials
Salbutamol sulfate (STS) was obtained from YaBang Co. Ltd. (Changzhou, China). Sodium carboxymethyl starch (CMS-Na; DMV, Veghel, The Netherlands), low-substituted hydroxypropyl cellulose (L-HPC; Shin-Etsu Company, Tokyo, Japan), lactose (BoDi Co. Ltd., Tianjin, China), polyvinylpyrrolidone (PVP; Fengli Jingqiu Commerce & Trade Co. Ltd., Tianjin, China), and magnesium stearate (BoDi Co. Ltd., Tianjin, China) were used for preparation of the core tablets. PEG 6000 (Kermel Chemical Reagents Development Centre, Tianjin, China), and Eudragit S100 (supplied as a gift by Degussa Co. Ltd., Shanghai Branch), were used for the outer shell of press-coated tablets. All other chemicals and solvents were standard pharmaceutical grade.
7. In vitro drug release studies
The dissolution study was performed according to the third method described in the part II of Pharmacopoeia of China (2005), with a rotation speed of 100 rpm. The dissolution media consisted of 100 mL of 0.1 M HCl for the first 2 h and pH 6.8 phosphate buffers for the following 7 h at 37 ± 0.5 °C. Samples of 5 mL were withdrawn at specified time intervals and filtered (0.45 μm). The concentrations of STS in sample solutions were analyzed at 276 nm for STS using a UV9100 spectrophotometer (Rili Analytical Instrument Co. Ltd., Beijing, China). An equivalent volume of temperature-equilibrated dissolution medium was replaced into the dissolution bath following the removal of each sample. The data represent the mean values of at least six separate experiments.
2. Preparation of the polymer blends as the barrier layer
PEG 6000-Eudragit S100 polymer blends (ratio in weight 1:1, 2:1, 3:1, 4:1, 5:1, 6:1 and 7:1) were prepared by fusion method as follows: the required amount of PEG 6000 was melted on a stainless-steel plate maintained in a water bath at 80-82 ºC and then Eudragit S100 was added under continuous stirring to the PEG solution. The mixture was stirred until a homogenate was obtained, and allowed to cool down at -20 ºC in refrigerator immediately for 1 h. Subsequently, the dispersions were smashed by FW100 universal high-speed smashing machine (Taisite Instrument Co. Ltd., Tianjin, China), and then sieved through a 380 μm sieve. The pulverized dispersions were stored in a desiccator at room temperature until use.
8. In vivo absorption studies in beagle dogs
The studies were carried out to compare pharmacokinetics of STS from the press-coated tablet to uncoated core tablet following an oral administration of 9.6 mg × 2 tablet using a single-dose, randomized, open, two-cross-over study and a wash-out period of 1 week. All animal studies were performed according to the Guidelines for the Care and Use of Laboratory Animals approved by the Ethics Committee of Animal Experimentation of Shenyang Pharmaceutical University. Five male beagle dogs with weight 10 ± 2 kg were used in this study. Dogs were fasted for 12 h before administration with free access to water. Each dog was given orally either reference (uncoated core tablets) or test formulation (press-coated STS tablets). The legs of the dogs were cannulated through the cephalic vein using a 22-gauge catheter. Venous blood samples were collected into heparinized centrifuge tubes before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h post-dosing for reference formulation. For test formulations, blood samples were collected into heparinized centrifuge tubes before dosing and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24 h after dosing. The blood samples were centrifuged at 3 000 r/min for 10 min to separate plasma. The samples were kept frozen at -20 °C until analysis.
3. Differential scanning calorimetric (DSC) analysis
Thermal analysis of the samples was performed on a Shimadzu DSC60 differential scanning calorimeter. For each measurement, a sample of approximately 6 mg was used, in sealed aluminum pans. All samples were run at a heating rate of 10 ºC/min over a temperature range 30-300 ºC in atmosphere of nitrogen.
4. Powder X-ray diffraction (PXRD)
Powder X-ray diffraction (PXRD) measurements were carried out on a Philips X’Pert powder diffractometer with Cu Kα radiation, carbon monochromator, voltage 50 kV, current 200 mA, scintillation detector. The diffraction patterns were recorded over a 2θ angular range of 3-40° with a step size of 2° in 2 θ and a 1 s counting per step at room temperature.
5. Preparation of core tablets
A wet granulation method was applied to prepare the granules for the core tablet. A powder mixture of 9.6 g STS, 10 g CMS-Na, 20 g L-HPC and 20 g lactose was kneaded with q.s. of 3 % (w:v) polyvinylpyrrolidone ethanol solution as the binder. The wetted mass was forced through a 920 μm screen. The granules were dried at 50 °C and then sized by passing through a 1060 μm screen. Next, 0.5 % magnesium stearate as a lubricant based on the total weight was added to the granules and mixed for 5 min so that particle surface was coated by lubricant evenly. The blend was compressed using a single punch tablet machine at a compression force of 4 kg/mm2 (Jingcheng Machine Manufacture Co. Ltd., Shandong, China). Concave punches 6 mm in diameter were used for the preparation of the core tablets, which contained 9.6 mg STS per 60 mg tablet.
9. HPLC assay
HPLC system equipped with a Shimadzu LC-10AT pump (Kyoto, Japan) and Agilent 1100 fluorescence detector (Agilent, Wilminton, DE, United States) was used for separation at 20 °C. The mobile phase consisted of acetonitrile-0.01 M sodium acetate (4.5:95.5, v/v, adjusted to pH 3.1 with glacial acetic acid) at a flow-rate of 0.8 mL/min through a Thermo Diamonsil column (C18, 5 μm, 200 × 4.6 mm, Zhonghuida, Dalian, China) with a security guard cartridge. Fluorescence detection at an excitation of 220 nm and emission of 310 nm and atenolol was used as an internal standard [11]. Frozen plasma samples from the dogs were thawed at room temperature prior to preparation. After vortexing 5 μL internal standard solution of atenolol (10 μg/mL in water) and 500 μL of buffer solution (pH 9.0) were added to 2 mL plasma samples. After vortexing, 5 mL 336
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
0.1 M di-(isooctyl)-phosphate in dichlormethane was added. The mixture was vortexed for 5 min and centrifuged at 4000 rpm for 10 min. The organic layer was transferred into to a centrifuge tube and 500 μL of 0.5 M phosphoric acid solution was added twice. The mixture was vortexed for 5 min and centrifuged at 4000 rpm for 10 min. The aqueous phase was transferred to another tube and centrifuged at 4000 rpm for 10 min. A 20 μL aliquot of the supernatant was injected onto the HPLC column. The retention time for STS and internal standard (atenolol) was about 6.5 min and 9.4 min, respectively. Calibration curve demonstrated linearity from 2.5 to 100 ng/mL. The lower limit of quantitation was 2.0 ng/mL and it was sufficient for pharmacokinetic studies. Precision was assessed by determining quality control (QC) samples at 2.5, 25 and 80 ng/mL on five different validation days. Both intra-run and inter-run precisions ranged from 2.41 to 2.92 % and from 3.02 to 3.55 % for each QC level, respectively.
2. Powder X-ray diffraction (PXRD)
The X-ray diffraction patterns for pure PEG 6000, Eudragit S100, the physical mixture and PEG 6000-Eudragit S100 polymer blend are depicted in Figure 2. PEG 6000 showed two sharp peaks at 19.3 and 23.5. The characteristic peaks of PEG 6000 and Eudragit S100 were also seen in the XRD pattern of the physical mixture, while in the XRD pattern for PEG 6000-Eudragit S100 polymer blend, the characteristic peaks of PEG 6000 and Eudragit S100 were all obviously weakened.
3. The effect of the weight ratio of PEG 6000 to Eudragit S100 on drug release
Figure 3 showed the effect of the weight ratio of PEG 6000 to Eudragit S100 on drug release in the dissolution media. The delay of the onset of the release was increased by decreasing the weight ratio of PEG 6000 to Eudragit S100 from 7:1 to 1:1 in the polymer complex. Since the dissolution profiles of STS from press-coated tablet showed a biphasic pattern, the lag times were defined as the time points at which the second rapid release of STS was initiated. In this study, the lag time of the second rapid release were calculated from the intersection of the linear portion of the dissolution profiles with the x-axis which represents the time scale. The lag time of 4 h seems to show an optimal value when the tablets are press-coated with PEG 6000/Eudragit dispersion in a blend of 2:1. The release of STS was less than 5 % after 2 h in acidic media and completed at 9 h in pH 6.8. Both a faster disruption and a quicker dissolution behavior was found for the press-coated tablet prepared by the weight ratio of PEG 6000-Eudragit S100 7:1 or 6:1 as out layer. The lag time was 2 h when the weight ratio of PEG 6000-Eudragit
10. Pharmacokinetic analysis
The peak concentration (Cmax) and the time to reach peak concentration (Tmax) were obtained directly from the measured values. The other pharmacokinetic parameters i.e., the half-life of elimination (t1/2), the elimination rate constant (Ke), the area under the plasma concentration-time curve until the last sampling time (AUC0-t) and the area from time 0 to infinity (AUC0-∞), were calculated by 3P97 computer program (issued by the State Food and Drug Administration of China for pharmacokinetic study).
II. Results 1. Differential scanning calorimetric (DSC) analysis
The DSC heating curves for Eudragit S100, PEG 6000, PEG 6000-Eudragit S100 polymer pulverized dispersions blend (2:1), and the physical mixture are shown in Figure 1. PEG 6000 and Eudragit S100 were weighed in a 2:1 ratio and then mixed by light trituration in a mortar to prepare the physical mixtures. The DSC scan of PEG 6000 showed an endothermic peak corresponding to the melting point of 65.86 °C. Eudragit S100 showed a broad transition at 69.77 °C, which appeared to be due to loss of water and this was not observed in the physical mixture or blend. Eudragit S100 showed a transition 213.9 °C and a weak transition at 250.41 °C. The physical mixtures exhibit endothermic peaks at 64.84 °C corresponding to PEG 6000. Furthermore, the DSC profile of blend made by fusion method exhibited a sharp endothermic peak at 59.23 °C, a small peak 249.85 °C. The distinct melting peak of PEG 6000 at 65.86 °C and Eudragit S100 at 213.9 °C was absent.
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Figure 2 - XRD patterns of (a) PEG 6000/Eudragit S100 2:1 polymer blend, (b) physical mixture, (c) Eudragit S100, (d) PEG 6000.
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Figure 3 - Release profiles of STS from press-coated tablets with various PEG 6000-Eudragit S100 ratios (n = 6).
Figure 1 - DSC patterns of (a) Eudragit S100, (b) PEG 6000, (c) PEG 6000-Eudragit S100 polymer blend, (d) physical mixture. 337
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
S100 was 5:1 and 4:1. But when tablets formulated using the weight ratio of PEG 6000-Eudragit S100 at 1:1 they did not show any coatinglayer swelling or erosion, so the drug release was uncompleted (about 40 % at 9 h).
4. Effect of the total coating weight PEG 6000 to Eudragit S100 (weight ratio 2:1) on drug release
Figure 4 shows the drug release behaviors in dissolution media from press-coated tablets with increasing coating weights. Each profile is characterized by a distinctive lag-time followed by a rapid drug release. The delay is increased from 2 to 6 h with increasing the outer coating layer weight from 0.12 to 0.20 g. When the weight of out layer is 0.20 g, it appears to slow down drug release which was incomplete at 9 h. Finally, the 0.15 g coating weight with PEG 6000-Eudragit S100 polymer ratio 2:1 was taken as the optimized formulation. As the drug release behavior showed, the release of STS was less than 5 % before 3 h and completed at 8 h in pH 6.8 phosphate buffer solution.
Figure 4 - Release profiles of STS from tablets with various coating weights of PEG 6000-Eudragit S100 2:1 (n = 6).
5. Dissolution results of STS core tablets
Figure 5 shows dissolution profiles of core tablet which did not have the out layer at dissolution media of 0.1 M HCl or pH 6.8 phosphate buffers. The core tablets can be dissolved in 0.1 M HCl or pH 6.8 phosphate buffer rapidly and reached 100 % in 6 min, because STS is a water-soluble drug.
6. Release mechanism
The release mechanism of STS from optimized press-coated tablet follows three different stages as Figure 6 shown: (a) in the first stage of dissolution, penetration of the dissolution media 0.1 M HCl is achieved leading to the expansion of the coating layer. The tablet is intact because of the existence of Eudragit S100; (b) in the second stage of the dissolution procedure, pH 6.8 buffer phosphate penetrated rapidly through the outer layer and the coating barrier is gradually eroded up to a limited thickness. A rupture of the out layer which was caused by the pressure rise up from the swelling of the active core is observed. This process corresponds to a lag time that enables a time-controlled release of the drug; (c) after the delay time, the third stage of dissolution corresponding to a rapid release of the drug takes place. A comprehensive and simple equation, Power law [12], which describes drug releases from polymeric systems, was applied to estimate the mechanism of drug release from this pulse release device: Mt/M∞ = k (t-T)n
Figure 5 - Dissolution profiles of core table at dissolution media of 0.1 M HCl or pH 6.8 phosphate buffers.
Figure 6 - Possible scheme for drug release from press-coated tablet.
Eq. 1
where Mt and M∞ are the absolute cumulative amounts of drug released at time t and infinite time, respectively; k is a constant incorporating structural and geometric characteristics of the device; T is lag time, and n is the release exponent, indicating the mechanism of drug release. For cylinders, n = 0.45 indicating Fickian diffusion-controlled drug release and n = 0.89 indicates bulk erosion-controlled drug release. Values of n between 0.45 and 0.89 can be regarded as an indicator for the superposition of both phenomena [13]. In this paper, the calculated release exponent, n, obtained by adapting Equation 1 to the observed data, is 2.389 [(Mt/M∞) = 0.645(t-T)2.389], indicating that bulk erosion is the mechanism of drug release in this paper.
7. In vivo evaluation of pharmacokinetic behavior of press-coated STS tablet and core tablet
Figure 7 - Profiles of mean plasma drug concentration-time of STS after an oral administration of press-coated tablet or core tablet containing 9.6 mg × 2 tablets STS to beagle dogs under fast condition (n = 5). Error bars represent means ± SD for each time.
No adverse reactions were observed during or after oral administration in any Beagle dog. The pharmacokinetic profiles of press-coated tablets analyzed by pharmacokinetic software 3P97 were conformed to the two compartment model. Mean values of pharmacokinetic parameters such as Cmax, Tmax, Ke, AUC0-t, AUC0-∞, t1/2 of core tablet and press-coated tablet as determined are summarized in Table I. A high 338
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
Table I - Efficiency of PDT treatment with different forms of chlorin e6 di-N-methylglucaminate on mice bearing Ehrlich tumor.
resulted in hydration and swelling of the erodible tablet and delayed drug-release pattern was observed. Thus, a sigmoidal release pattern was observed from the designed formulations suitable for sustained delivery. In this study, 4 h lag time of the second rapid release was calculated from the intersection of the linear portion of the dissolution profiles with the x-axis which represents the time scale [15]. Finally, the 0.15 g coating weight with PEG 6000-Eudragit S100 polymer ratio 2:1 was taken as the optimized formulation for further pharmacokinetic behavior evaluation in Beagle dogs. These results of the dissolution tests show that blending Eudragit S 100 and PEG 6000 at a suitable weight is a useful approach to control the delayed release pattern of STS. The observation of the prepared tablets during the dissolution procedure revealed that the out layer, composed of PEG 6000-Eudragit S100 blend, is indeed a rupturable and erodible barrier. The studied blends have a satisfying delayed drug-release property, which is essential in order to be used as an effective press-coating barrier for the creation of delayed-release formulations. In vivo evaluation in Beagle dogs revealed that STS in press-coated tablet first appeared in the systemic circulation at 3 h after administration corresponding to the in vitro release behavior. In conclusion, salbutamol sulfate press-coated tablets were successfully formulated by polymer blends consisting of PEG 6000 and Eudragit S100 as an outer layer.
Groups
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In aqueous solution In liposomal dispersion
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8
11
15
18
23
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48 58
39 61
44 76
48 83
57 86
inter-subject variability was observed in the concentration-time curves obtained in this study. The mean serum concentration-time profiles of press-coated STS tablet and core tablet are presented in Figure 7. For the immediate release, STS appear in the systemic circulation at 15 min and its Cmax was about 9.6 ng·mL-1 achieved at 1.83 h after oral administration in beagle dogs. STS is known to be quickly absorbed via the intestinal wall and appeared in systemic circulation. STS from the optimized press coated tablet first appeared in the systemic circulation at 3 h after administration corresponding to the in vitro release behavior.
III. Discussion
Oral delayed-release formulations are designed to modify drug release in order to optimize drug therapy and hence improve patient compliance. Researchers have focused on designing oral timed-release drug delivery systems for the treatment of diseases which follow circadian rhythm. Hence, medications needed for the management of such disease conditions should be administered at the necessary time to maintain a therapeutic blood level in the body system. The delayed-release tablet system developed in the present study was a reservoir device, where the tablet cores were coated by PEG 6000 and Eudragit S100 dispersion blends. The blends made by fusion method were characterized using DSC and PXRD. The difference of the dispersion blend from that of individual polymers and physical mixture indicated that the two polymers are completely miscibility and a new polymer matrix was formed. PEG 6000 is melt while Eudragit S 100 is in a dispersed state and the polymer to form a continuous matrix. PEG 6000-Eudragit S100 polymer pulverized dispersions blend was used to modulate the release STS from the press-coated tablet. STS release from core tablets which did not have the outer layer was complete within 10 min, since there was no barrier to delay dissolution. This is in agreement with another study which showed that lag time is a function of the thickness when polymer used for coating is not completely soluble [14] The active erosion rate of the outer barrier layer depends upon the weight ratio, which in turn determines the sustained release of the STS. The drug release from press-coated tablet increased as the ratio of Eudragit S100 to PEG 6000 in the fusion process used as barrier layer increased. A possible explanation could be that when the ratio of PEG 6000 hydrophilic carrier incorporated in the blends is in a higher ratio, the initial flux of dissolution medium absorbed into the out powder layer leads to a much more permeable, and hence, quicker rupture. This suggests that PEG 6000 might possibly be acting as a pore-forming agent in the outer layer at dissolution medium, thus enhancing the penetration of water before rupturing the surrounding outer layer. In other words, the release of STS in 0.1 M HCl media decreased with an increasing amount of Eudragit S100, which correlates well with the fact that the Eudragit S100 is soluble at pH-values higher than 7.0. A very low amount of drug in the optimized formulation was released in the initial period in acidic to weakly acidic medium. This was due to the fact that the barrier-layers hindered the penetration of liquid into the core and modified drug release remained intact. However, with increase of pH, dissolution of PEG 6000/Eudragit S100 blends
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J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
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Urbinati G., Audisio D., Marsaud V., Plassat V., Arpicco S., Sola B., Fattal E., Renoir J.M. - Therapeutic potential of new 4-hydroxy-tamoxifen-loaded pH-gradient liposomes in a multiple myeloma experimental model. - Pharm. Res., 27 (2), 327-339, 2010. Zagainova E.V., Shirmanova M.V., Sirotkina M.A., Balalayeva I.V., Kleshnin M.S., Turchin I.V., Sedakova L.A., Romanenko V.I., Treshalina E.M. - Monitoring of accumulation of photosensitizers in tumor by method of diffuse and fluorescent tomography. - Russian Biotherapeutic Journal, 7 (4), 30-35, 2008. Awasthi V.D., Garcia D., Goins B.A., Phillips W.T. - Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits. - Int. J. Pharm., 253 (1-2), 121-132, 2003. Bangham A.D., Standish M.M., Watkins J.C. - Diffusion of univalent ions across the lamellae of swollen phospholipids. Journal of Molecular Biology, 13, 238-252, 1965.
Authors wish to acknowledge the Liaoning Science and Technology Commission for financial support (No. 20091080).
Manuscript Received 13 September 2011, accepted for publication 3 January 2012.
340
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang1§, P. Cui2§, Q. Luo1, L. Wang1, S. Li1, X. Zhang1* 1
Shenyang Pharmaceutical University, Wen Hua Road, No. 103, Shenyang 110016, Liaoning Province, China 2 The first hospital of China Medical University, Shenyang 110001, Liaoning Province, China § These authors contributed equally to this work. *Correspondence: [email protected]
The purpose of this work was to develop optimized press-coated tablets of salbutamol sulfate using polyethylene glycol 6000 (PEG 6000)-Eudragit S100 dispersion blends in the outer shell. To facilitate the direct application of the Eudragit S100 and PEG 6000 onto the inner core, solid Eudragit S100 powder was mixed with PEG 6000 by fusion method. The optimized, pulverized dispersions of polymer blends were evaluated by various methods of characterization, including differential scanning calorimetry, X-ray diffraction and spectroscopy. The press-coated tablets containing salbutamol sulfate in the inner core were prepared by compression-coating with (PEG 6000)-Eudragit S100 dispersion blends as the outer layer in different ratios. The amount of outer layer on the delayed drug release was investigated. The press-coated tablets release were evaluated in 0.1 M HCl for the first 2 h and then in pH 6.8 phosphate buffer for 7 h. The mechanism of delayed drug release is based on erosion of the out layer blends. The results showed the 0.15 g of PEG 6000/ Eudragit S100 (2:1) in the outer shell achieving delayed release of drug in vitro as well as in the plasma of beagle dogs. Key words: Salbutamol sulfate – Press-coated tablet – PEG 6000-Eudragit S100 blends – Dissolution – Delayed release – In vitro, in vivo – Beagle dogs.
Salbutamol sulfate (STS) is one of the most widely used drugs for the treatment of bronchial asthma, chronic bronchitis and emphysema [1]. As an adrenergic agonist, it is an effective bronchodilator following peroral administration. The drug undergoes extensive first-pass metabolism and thus requires frequent administrations by the oral route. Asthma is a chronic disease, and since most of the patients suffer nocturnally, it is inconvenient for patients to take the medicine at midnight [2]. There is a need for a special designed drug delivery system which can maintain concentrations of STS at a therapeutic level for a long time. Delayed drug delivery systems can be categorized into a sitespecific or time-controlled system. A site specific system is typically controlled by environmental factors, such as pH or enzymes [3, 4]. In time-controlled systems, drug release is controlled primarily by the design of the delivery system. Time-controlled systems are characterized by two release phases. An initial phase when little drug is released, followed by a second phase, during which the drug is released completely within a short period of time after a lag [5]. Time-controlled release formulation is the preferred approach for the treatment of circadian diseases such as asthma, rheumatic arthritis or inflammation. Time-controlled release formulation generally has a rapid-release tablet core encompassed by a barrier layer formed by press-coating, polymer coating or a combination of both [6]. Compared with polymer coating, press-coating technique has the advantage of not needing to use solvents and a relatively short manufacturing process. Delayed drug release from press-coated tablets depends on the thickness and the composition of the barrier layer. Generally, the thicker the barrier layer, the longer the time there is for drug release [7]. Composition of the barrier layer controls the mechanism affecting the drug release. Polymer blends could be the solution for the creation of new materials, exhibiting the appropriate flexibility for the adjustment of the drug release [8]. In the current study, polymer blends consisting of polyethylene glycol 6000 (PEG 6000) and Eudragit S100 are investigated to create a
system that can be modified by taking advantage of the hydrophilicity of PEG 6000 and hydrophobicity of Eudragit S100 in 0.1 M HCl. The pulverized dispersions of polymer blends were mechanically much stronger than the physical mixture of Eudragit S100 and PEG 6000. The combination and application of PEG 6000-Eudragit S100 blends as press-coating material is novel in the drug delivery field, since there is no such report to date in the literature. The press-coated tablet does not release the drug in the stomach due to the acid resistance of the outer coating layer containing Eudragit S100. After gastric emptying, the intestinal fluid begins to slowly erode the press-coated PEG 6000-Eudragit S100 layer, and when the erosion front reaches the core tablet, rapid drug release occurs. The delayed release time can be controlled by the weight or composition of the PEG 6000-Eudragit S100 miscible blends for the outer layer. The dog is widely used for in vivo evaluation of delayed-release formulation because of its reported similarity in gastrointestinal anatomy and motility. The use of the dog is further advantageous in terms of being less expensive and more readily available than conducting studies in human volunteers [9, 10]. A further objective of the present study therefore was to investigate in vivo performance of the STS press-coated tablet. The purpose of this investigation was to prepare PEG 6000-Eudragit S100 polymer blends used in delayed release formulations of STS press-coated tablets. The internal core contains the active pharmaceutical ingredient (STS) while the external homogeneous coating layer is composed of various PEG 6000-Eudragit S100 blends made by fusion method that adjust to the initiation of STS release through their rupture. PEG 6000 was used as a hydrophilic carrier to prepare the dispersions due to its low melting point, high viscosity, rapid solidification rate and wide compatibility. Eudragit S100 is an enteric coating polymer, composed of methyl-methacrylate and methacrylic acid. This polymer is soluble at pH-values higher than 7.0. It is slowly soluble in the region of the digestive tract where juices are neutral to weakly alkaline. The coating layer consisted of Eudragit S100, resistant to the conditions in the stomach, and PEG 6000 as hydrophilic carrier, 335
J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
to ensure the complete release of drug within the pH range of 6.0-7.0 during transit through the small intestine. The objective of the current study was to evaluate the in vitro performance of the press-coated tablets for delayed release formulation and the in vivo behavior after an oral administration to beagle dogs under fast condition.
6. Coating core tablets with PEG 6000-Eudragit S100 blends
The active core contains active STS while the coating layer is composed of the various polymer blends of Eudragit S100 with PEG 6000. The press coated tablets were prepared by direct compression technique. Eudragit S100 with PEG 6000 pulverized dispersions were accurately weighed. 0.5 % magnesium stearate as a lubricant based on out layer weight was added to the dried granules and passed through a sieve of 500 μm aperture size and mixed for 5 min. Half the amount of polymer granules was filled into the die, and a core tablet was placed at the center on the polymer. Then, the remaining half was filled in the die, and the total contents were compressed to form a biconvex tablet with a diameter of 9 mm, at a compression force of 3 kg/mm2 using single punch tablet machine. Thickness of coating layer is about 1.3-1.4 mm.
I. Materials and Methods 1. Materials
Salbutamol sulfate (STS) was obtained from YaBang Co. Ltd. (Changzhou, China). Sodium carboxymethyl starch (CMS-Na; DMV, Veghel, The Netherlands), low-substituted hydroxypropyl cellulose (L-HPC; Shin-Etsu Company, Tokyo, Japan), lactose (BoDi Co. Ltd., Tianjin, China), polyvinylpyrrolidone (PVP; Fengli Jingqiu Commerce & Trade Co. Ltd., Tianjin, China), and magnesium stearate (BoDi Co. Ltd., Tianjin, China) were used for preparation of the core tablets. PEG 6000 (Kermel Chemical Reagents Development Centre, Tianjin, China), and Eudragit S100 (supplied as a gift by Degussa Co. Ltd., Shanghai Branch), were used for the outer shell of press-coated tablets. All other chemicals and solvents were standard pharmaceutical grade.
7. In vitro drug release studies
The dissolution study was performed according to the third method described in the part II of Pharmacopoeia of China (2005), with a rotation speed of 100 rpm. The dissolution media consisted of 100 mL of 0.1 M HCl for the first 2 h and pH 6.8 phosphate buffers for the following 7 h at 37 ± 0.5 °C. Samples of 5 mL were withdrawn at specified time intervals and filtered (0.45 μm). The concentrations of STS in sample solutions were analyzed at 276 nm for STS using a UV9100 spectrophotometer (Rili Analytical Instrument Co. Ltd., Beijing, China). An equivalent volume of temperature-equilibrated dissolution medium was replaced into the dissolution bath following the removal of each sample. The data represent the mean values of at least six separate experiments.
2. Preparation of the polymer blends as the barrier layer
PEG 6000-Eudragit S100 polymer blends (ratio in weight 1:1, 2:1, 3:1, 4:1, 5:1, 6:1 and 7:1) were prepared by fusion method as follows: the required amount of PEG 6000 was melted on a stainless-steel plate maintained in a water bath at 80-82 ºC and then Eudragit S100 was added under continuous stirring to the PEG solution. The mixture was stirred until a homogenate was obtained, and allowed to cool down at -20 ºC in refrigerator immediately for 1 h. Subsequently, the dispersions were smashed by FW100 universal high-speed smashing machine (Taisite Instrument Co. Ltd., Tianjin, China), and then sieved through a 380 μm sieve. The pulverized dispersions were stored in a desiccator at room temperature until use.
8. In vivo absorption studies in beagle dogs
The studies were carried out to compare pharmacokinetics of STS from the press-coated tablet to uncoated core tablet following an oral administration of 9.6 mg × 2 tablet using a single-dose, randomized, open, two-cross-over study and a wash-out period of 1 week. All animal studies were performed according to the Guidelines for the Care and Use of Laboratory Animals approved by the Ethics Committee of Animal Experimentation of Shenyang Pharmaceutical University. Five male beagle dogs with weight 10 ± 2 kg were used in this study. Dogs were fasted for 12 h before administration with free access to water. Each dog was given orally either reference (uncoated core tablets) or test formulation (press-coated STS tablets). The legs of the dogs were cannulated through the cephalic vein using a 22-gauge catheter. Venous blood samples were collected into heparinized centrifuge tubes before dosing and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h post-dosing for reference formulation. For test formulations, blood samples were collected into heparinized centrifuge tubes before dosing and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24 h after dosing. The blood samples were centrifuged at 3 000 r/min for 10 min to separate plasma. The samples were kept frozen at -20 °C until analysis.
3. Differential scanning calorimetric (DSC) analysis
Thermal analysis of the samples was performed on a Shimadzu DSC60 differential scanning calorimeter. For each measurement, a sample of approximately 6 mg was used, in sealed aluminum pans. All samples were run at a heating rate of 10 ºC/min over a temperature range 30-300 ºC in atmosphere of nitrogen.
4. Powder X-ray diffraction (PXRD)
Powder X-ray diffraction (PXRD) measurements were carried out on a Philips X’Pert powder diffractometer with Cu Kα radiation, carbon monochromator, voltage 50 kV, current 200 mA, scintillation detector. The diffraction patterns were recorded over a 2θ angular range of 3-40° with a step size of 2° in 2 θ and a 1 s counting per step at room temperature.
5. Preparation of core tablets
A wet granulation method was applied to prepare the granules for the core tablet. A powder mixture of 9.6 g STS, 10 g CMS-Na, 20 g L-HPC and 20 g lactose was kneaded with q.s. of 3 % (w:v) polyvinylpyrrolidone ethanol solution as the binder. The wetted mass was forced through a 920 μm screen. The granules were dried at 50 °C and then sized by passing through a 1060 μm screen. Next, 0.5 % magnesium stearate as a lubricant based on the total weight was added to the granules and mixed for 5 min so that particle surface was coated by lubricant evenly. The blend was compressed using a single punch tablet machine at a compression force of 4 kg/mm2 (Jingcheng Machine Manufacture Co. Ltd., Shandong, China). Concave punches 6 mm in diameter were used for the preparation of the core tablets, which contained 9.6 mg STS per 60 mg tablet.
9. HPLC assay
HPLC system equipped with a Shimadzu LC-10AT pump (Kyoto, Japan) and Agilent 1100 fluorescence detector (Agilent, Wilminton, DE, United States) was used for separation at 20 °C. The mobile phase consisted of acetonitrile-0.01 M sodium acetate (4.5:95.5, v/v, adjusted to pH 3.1 with glacial acetic acid) at a flow-rate of 0.8 mL/min through a Thermo Diamonsil column (C18, 5 μm, 200 × 4.6 mm, Zhonghuida, Dalian, China) with a security guard cartridge. Fluorescence detection at an excitation of 220 nm and emission of 310 nm and atenolol was used as an internal standard [11]. Frozen plasma samples from the dogs were thawed at room temperature prior to preparation. After vortexing 5 μL internal standard solution of atenolol (10 μg/mL in water) and 500 μL of buffer solution (pH 9.0) were added to 2 mL plasma samples. After vortexing, 5 mL 336
Development and evaluation of press-coated salbutamol sulfate tablet for delayed-release dosage forms J. Wang, P. Cui, Q. Luo, L. Wang, S. Li, X. Zhang
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0.1 M di-(isooctyl)-phosphate in dichlormethane was added. The mixture was vortexed for 5 min and centrifuged at 4000 rpm for 10 min. The organic layer was transferred into to a centrifuge tube and 500 μL of 0.5 M phosphoric acid solution was added twice. The mixture was vortexed for 5 min and centrifuged at 4000 rpm for 10 min. The aqueous phase was transferred to another tube and centrifuged at 4000 rpm for 10 min. A 20 μL aliquot of the supernatant was injected onto the HPLC column. The retention time for STS and internal standard (atenolol) was about 6.5 min and 9.4 min, respectively. Calibration curve demonstrated linearity from 2.5 to 100 ng/mL. The lower limit of quantitation was 2.0 ng/mL and it was sufficient for pharmacokinetic studies. Precision was assessed by determining quality control (QC) samples at 2.5, 25 and 80 ng/mL on five different validation days. Both intra-run and inter-run precisions ranged from 2.41 to 2.92 % and from 3.02 to 3.55 % for each QC level, respectively.
2. Powder X-ray diffraction (PXRD)
The X-ray diffraction patterns for pure PEG 6000, Eudragit S100, the physical mixture and PEG 6000-Eudragit S100 polymer blend are depicted in Figure 2. PEG 6000 showed two sharp peaks at 19.3 and 23.5. The characteristic peaks of PEG 6000 and Eudragit S100 were also seen in the XRD pattern of the physical mixture, while in the XRD pattern for PEG 6000-Eudragit S100 polymer blend, the characteristic peaks of PEG 6000 and Eudragit S100 were all obviously weakened.
3. The effect of the weight ratio of PEG 6000 to Eudragit S100 on drug release
Figure 3 showed the effect of the weight ratio of PEG 6000 to Eudragit S100 on drug release in the dissolution media. The delay of the onset of the release was increased by decreasing the weight ratio of PEG 6000 to Eudragit S100 from 7:1 to 1:1 in the polymer complex. Since the dissolution profiles of STS from press-coated tablet showed a biphasic pattern, the lag times were defined as the time points at which the second rapid release of STS was initiated. In this study, the lag time of the second rapid release were calculated from the intersection of the linear portion of the dissolution profiles with the x-axis which represents the time scale. The lag time of 4 h seems to show an optimal value when the tablets are press-coated with PEG 6000/Eudragit dispersion in a blend of 2:1. The release of STS was less than 5 % after 2 h in acidic media and completed at 9 h in pH 6.8. Both a faster disruption and a quicker dissolution behavior was found for the press-coated tablet prepared by the weight ratio of PEG 6000-Eudragit S100 7:1 or 6:1 as out layer. The lag time was 2 h when the weight ratio of PEG 6000-Eudragit
10. Pharmacokinetic analysis
The peak concentration (Cmax) and the time to reach peak concentration (Tmax) were obtained directly from the measured values. The other pharmacokinetic parameters i.e., the half-life of elimination (t1/2), the elimination rate constant (Ke), the area under the plasma concentration-time curve until the last sampling time (AUC0-t) and the area from time 0 to infinity (AUC0-∞), were calculated by 3P97 computer program (issued by the State Food and Drug Administration of China for pharmacokinetic study).
II. Results 1. Differential scanning calorimetric (DSC) analysis
The DSC heating curves for Eudragit S100, PEG 6000, PEG 6000-Eudragit S100 polymer pulverized dispersions blend (2:1), and the physical mixture are shown in Figure 1. PEG 6000 and Eudragit S100 were weighed in a 2:1 ratio and then mixed by light trituration in a mortar to prepare the physical mixtures. The DSC scan of PEG 6000 showed an endothermic peak corresponding to the melting point of 65.86 °C. Eudragit S100 showed a broad transition at 69.77 °C, which appeared to be due to loss of water and this was not observed in the physical mixture or blend. Eudragit S100 showed a transition 213.9 °C and a weak transition at 250.41 °C. The physical mixtures exhibit endothermic peaks at 64.84 °C corresponding to PEG 6000. Furthermore, the DSC profile of blend made by fusion method exhibited a sharp endothermic peak at 59.23 °C, a small peak 249.85 °C. The distinct melting peak of PEG 6000 at 65.86 °C and Eudragit S100 at 213.9 °C was absent.
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Figure 3 - Release profiles of STS from press-coated tablets with various PEG 6000-Eudragit S100 ratios (n = 6).
Figure 1 - DSC patterns of (a) Eudragit S100, (b) PEG 6000, (c) PEG 6000-Eudragit S100 polymer blend, (d) physical mixture. 337
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S100 was 5:1 and 4:1. But when tablets formulated using the weight ratio of PEG 6000-Eudragit S100 at 1:1 they did not show any coatinglayer swelling or erosion, so the drug release was uncompleted (about 40 % at 9 h).
4. Effect of the total coating weight PEG 6000 to Eudragit S100 (weight ratio 2:1) on drug release
Figure 4 shows the drug release behaviors in dissolution media from press-coated tablets with increasing coating weights. Each profile is characterized by a distinctive lag-time followed by a rapid drug release. The delay is increased from 2 to 6 h with increasing the outer coating layer weight from 0.12 to 0.20 g. When the weight of out layer is 0.20 g, it appears to slow down drug release which was incomplete at 9 h. Finally, the 0.15 g coating weight with PEG 6000-Eudragit S100 polymer ratio 2:1 was taken as the optimized formulation. As the drug release behavior showed, the release of STS was less than 5 % before 3 h and completed at 8 h in pH 6.8 phosphate buffer solution.
Figure 4 - Release profiles of STS from tablets with various coating weights of PEG 6000-Eudragit S100 2:1 (n = 6).
5. Dissolution results of STS core tablets
Figure 5 shows dissolution profiles of core tablet which did not have the out layer at dissolution media of 0.1 M HCl or pH 6.8 phosphate buffers. The core tablets can be dissolved in 0.1 M HCl or pH 6.8 phosphate buffer rapidly and reached 100 % in 6 min, because STS is a water-soluble drug.
6. Release mechanism
The release mechanism of STS from optimized press-coated tablet follows three different stages as Figure 6 shown: (a) in the first stage of dissolution, penetration of the dissolution media 0.1 M HCl is achieved leading to the expansion of the coating layer. The tablet is intact because of the existence of Eudragit S100; (b) in the second stage of the dissolution procedure, pH 6.8 buffer phosphate penetrated rapidly through the outer layer and the coating barrier is gradually eroded up to a limited thickness. A rupture of the out layer which was caused by the pressure rise up from the swelling of the active core is observed. This process corresponds to a lag time that enables a time-controlled release of the drug; (c) after the delay time, the third stage of dissolution corresponding to a rapid release of the drug takes place. A comprehensive and simple equation, Power law [12], which describes drug releases from polymeric systems, was applied to estimate the mechanism of drug release from this pulse release device: Mt/M∞ = k (t-T)n
Figure 5 - Dissolution profiles of core table at dissolution media of 0.1 M HCl or pH 6.8 phosphate buffers.
Figure 6 - Possible scheme for drug release from press-coated tablet.
Eq. 1
where Mt and M∞ are the absolute cumulative amounts of drug released at time t and infinite time, respectively; k is a constant incorporating structural and geometric characteristics of the device; T is lag time, and n is the release exponent, indicating the mechanism of drug release. For cylinders, n = 0.45 indicating Fickian diffusion-controlled drug release and n = 0.89 indicates bulk erosion-controlled drug release. Values of n between 0.45 and 0.89 can be regarded as an indicator for the superposition of both phenomena [13]. In this paper, the calculated release exponent, n, obtained by adapting Equation 1 to the observed data, is 2.389 [(Mt/M∞) = 0.645(t-T)2.389], indicating that bulk erosion is the mechanism of drug release in this paper.
7. In vivo evaluation of pharmacokinetic behavior of press-coated STS tablet and core tablet
Figure 7 - Profiles of mean plasma drug concentration-time of STS after an oral administration of press-coated tablet or core tablet containing 9.6 mg × 2 tablets STS to beagle dogs under fast condition (n = 5). Error bars represent means ± SD for each time.
No adverse reactions were observed during or after oral administration in any Beagle dog. The pharmacokinetic profiles of press-coated tablets analyzed by pharmacokinetic software 3P97 were conformed to the two compartment model. Mean values of pharmacokinetic parameters such as Cmax, Tmax, Ke, AUC0-t, AUC0-∞, t1/2 of core tablet and press-coated tablet as determined are summarized in Table I. A high 338
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J. DRUG DEL. SCI. TECH., 22 (4) 335-340 2012
Table I - Efficiency of PDT treatment with different forms of chlorin e6 di-N-methylglucaminate on mice bearing Ehrlich tumor.
resulted in hydration and swelling of the erodible tablet and delayed drug-release pattern was observed. Thus, a sigmoidal release pattern was observed from the designed formulations suitable for sustained delivery. In this study, 4 h lag time of the second rapid release was calculated from the intersection of the linear portion of the dissolution profiles with the x-axis which represents the time scale [15]. Finally, the 0.15 g coating weight with PEG 6000-Eudragit S100 polymer ratio 2:1 was taken as the optimized formulation for further pharmacokinetic behavior evaluation in Beagle dogs. These results of the dissolution tests show that blending Eudragit S 100 and PEG 6000 at a suitable weight is a useful approach to control the delayed release pattern of STS. The observation of the prepared tablets during the dissolution procedure revealed that the out layer, composed of PEG 6000-Eudragit S100 blend, is indeed a rupturable and erodible barrier. The studied blends have a satisfying delayed drug-release property, which is essential in order to be used as an effective press-coating barrier for the creation of delayed-release formulations. In vivo evaluation in Beagle dogs revealed that STS in press-coated tablet first appeared in the systemic circulation at 3 h after administration corresponding to the in vitro release behavior. In conclusion, salbutamol sulfate press-coated tablets were successfully formulated by polymer blends consisting of PEG 6000 and Eudragit S100 as an outer layer.
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inter-subject variability was observed in the concentration-time curves obtained in this study. The mean serum concentration-time profiles of press-coated STS tablet and core tablet are presented in Figure 7. For the immediate release, STS appear in the systemic circulation at 15 min and its Cmax was about 9.6 ng·mL-1 achieved at 1.83 h after oral administration in beagle dogs. STS is known to be quickly absorbed via the intestinal wall and appeared in systemic circulation. STS from the optimized press coated tablet first appeared in the systemic circulation at 3 h after administration corresponding to the in vitro release behavior.
III. Discussion
Oral delayed-release formulations are designed to modify drug release in order to optimize drug therapy and hence improve patient compliance. Researchers have focused on designing oral timed-release drug delivery systems for the treatment of diseases which follow circadian rhythm. Hence, medications needed for the management of such disease conditions should be administered at the necessary time to maintain a therapeutic blood level in the body system. The delayed-release tablet system developed in the present study was a reservoir device, where the tablet cores were coated by PEG 6000 and Eudragit S100 dispersion blends. The blends made by fusion method were characterized using DSC and PXRD. The difference of the dispersion blend from that of individual polymers and physical mixture indicated that the two polymers are completely miscibility and a new polymer matrix was formed. PEG 6000 is melt while Eudragit S 100 is in a dispersed state and the polymer to form a continuous matrix. PEG 6000-Eudragit S100 polymer pulverized dispersions blend was used to modulate the release STS from the press-coated tablet. STS release from core tablets which did not have the outer layer was complete within 10 min, since there was no barrier to delay dissolution. This is in agreement with another study which showed that lag time is a function of the thickness when polymer used for coating is not completely soluble [14] The active erosion rate of the outer barrier layer depends upon the weight ratio, which in turn determines the sustained release of the STS. The drug release from press-coated tablet increased as the ratio of Eudragit S100 to PEG 6000 in the fusion process used as barrier layer increased. A possible explanation could be that when the ratio of PEG 6000 hydrophilic carrier incorporated in the blends is in a higher ratio, the initial flux of dissolution medium absorbed into the out powder layer leads to a much more permeable, and hence, quicker rupture. This suggests that PEG 6000 might possibly be acting as a pore-forming agent in the outer layer at dissolution medium, thus enhancing the penetration of water before rupturing the surrounding outer layer. In other words, the release of STS in 0.1 M HCl media decreased with an increasing amount of Eudragit S100, which correlates well with the fact that the Eudragit S100 is soluble at pH-values higher than 7.0. A very low amount of drug in the optimized formulation was released in the initial period in acidic to weakly acidic medium. This was due to the fact that the barrier-layers hindered the penetration of liquid into the core and modified drug release remained intact. However, with increase of pH, dissolution of PEG 6000/Eudragit S100 blends
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5.
6. 7.
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9. 10.
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Authors wish to acknowledge the Liaoning Science and Technology Commission for financial support (No. 20091080).
Manuscript Received 13 September 2011, accepted for publication 3 January 2012.
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